Comparison of venous abnormalities using both catheter venography and ultrasound imaging shows little difference among patients with multiple sclerosis (MS), their unaffected siblings, and healthy unrelated controls, according to a studypublished online October 9, 2013, ahead of print in the Lancet. The findings appear todiscredit a controversial theory that has been embraced by many MS patients.

The original data supporting the theory came from a study led by Paolo Zamboni, MD, ofAzienda Ospedaliero-Universitaria di Ferrara (Ferrara, Italy), which reported evidence of what he termed chronic cerebrospinal venous insufficiency (CCSVI) in patients with MS but not in control subjects (J Neurol Sci. 2009;282:21-27). A number of researchers have since been unable to verify the results of either that initial study or another in which Dr. Zamboni reported disease phenotype-specific venous outflow characteristics in MS patients and suggested that endovascular treatment of the stenosis could have a beneficial effect on MS symptoms.

For the current case-control study, investigators led by Anthony L. Taboulsee, MD, of the University of British Columbia Hospital (Vancouver, Canada), recruited 177 adults at 3 Canadian centers: 79 with MS, 55 unaffected siblings, and 43 unrelated healthy controls.

To evaluate the morphology and function of the internal jugular and azygous veins as well as the validity of Dr. Zamboni’s CCSVI criteria, 171 subjects received ultrasound, 149 underwent catheter venography, and 143 had both imaging procedures.

Ultrasound, Catheter Venography Criteria Tested

Using ultrasound criteria for CCSVI, blinded sonographers correctly identified MS in 37 of 82 cases (45%) and responded “no idea” in 16 cases (20%). However, when catheter venography was applied to these criteria in 78 of 149 cases (52%), radiologists could not determine MS status. Using Dr. Zamboni’s catheter venography classification of CCSVI, the investigators identified only 1 subject in each group who fit the criteria. In addition, similar proportions of patients in all 3 groups met a simplified criterion of more than 50% narrowing in any major extracranial vein on catheter venography. The same pattern was seen when flow abnormalities were added to narrowing, although the percentages declined across the groups (table 1).

MS Patients

Unaffected Siblings

Unrelated Healthy Controls

P Value

Siblings vs. Controls

Siblings vs. MS Pts

MS Pts vs. Controls

Ultrasound≥2 of 5 Criteria Positive

44%

31%

45%

0.27

0.15

0.98

Zamboni VenographyCriteria

2%

2%

3%

1.0

1.0

1.0

≥ 50% Narrowing on Venography

74%

66%

70%

0.81

0.41

0.82

≥ 50% Narrowing with Abnormal Flow

51%

45%

54%

0.51

0.57

0.88

Overall, 5% of MS patients (as well as 17% of siblings and 11% of controls) did not meet any of the 5 Zamboni criteria for CCSVI. There was no indication that sex, age, or study site had any effect on ultrasound findings (P < 0.3).

In addition, ultrasound criteria for CCSVI showed poor agreement with catheter venography criteria for CCSVI and for narrowing with or without flow abnormality, both in participants with MS and healthy controls.

In an accompanying editorial, Friedemann Paul, MD, of Charité-Universitätsmedizin Berlin (Berlin, Germany) and Mike P. Wattjes, MD, of VU University Medical Center(Amsterdam, The Netherlands), highlight the study’s combined use of ultrasound and catheter venography, “which is widely regarded as the gold standard for this type of diagnosis.”

According to the editorial, the findings show that CCSVI is not highly prevalent in MS patients and is neither specific to the disease nor does it play a causative role. “What has been described as venous narrowing is unlikely to be more than frequent anatomical variants of a complex vascular system that remains poorly understood,” Drs. Paul and Wattjes write.

In short, the editorial declares, the study sounds the “death knell for the hypothesis of [CCSVI] as a disease entity.”

Research Aimed at Guiding Patients

In a press briefing, Dr. Traboulsee said the research was motivated by the need to provide informed answers to patients whose hopes have been raised by publicity surrounding so-called ‘liberation’ treatment for MS (ie, venous stenting).

One of the main criticisms of Dr. Zamboni’s studies was lack of blinding, he said, so “we wanted to ensure that we controlled for bias with a fully blinded study.” Another limitation of earlier CCSVI studies is that they used ultrasound or MRI, which do not look directly at the veins, he noted, adding that this study is the first to employ catheter venography.

The fact that only 3 subjects met Dr. Zamboni’s catheter venography criteria for CCSVI was “a big surprise,” Dr. Traboulsee commented. “We wondered whether clinics that were treating MS patients were using a different, ‘real world’ definition of CCSVI. We defined that as neck vein narrowing of more than 50%.” Although such narrowing was evident in about three-quarters of participants it was almost equally distributed across all 3 groups, he said.

The conclusion is that narrowing of the internal jugular and azygous veins is common and probably normal in most people. That makes sense, Dr. Traboulsee commented, because vein anatomy is highly variable.

Angioplasty: ‘Simplistic’ or Still Worth Investigating?

In an e-mail communication with TCTMD, Adnan H. Siddiqui, MD, PhD, of the University at Buffalo (Buffalo, NY),said that this study of CCSVI as “an initial foray into venous anatomy and function” should be applauded. He agreed that most venous narrowings are not physiologically important, but added that in his recent PREMiSe (Prospective Randomized Endovascular Therapy in MS) study he found suggestions of venous reflux and more anomalies on IVUS than were detected by catheter venography.

The current study is “by no means a death knell” for the field, Dr. Siddiqui countered, but he added that current evidence argues against use of “a simplistic procedure such as venous angioplasty,” which “has no benefit and may do harm in patients with MS.”

Nonetheless, Canadian investigators are proceeding with a randomized trial of endovascular neck vein therapy, Dr. Traboulsee reported. “We’re basing this on observation and patients’ reports of benefit,” he said. “If we separate that from the [faulty CCSVI] theory, I think it justifies going forward.”

Disclosures

The study was funded by the Lotte and John Hecht Memorial Foundation, the MS Society of Canada, the Saskatoon City Hospital Foundation, the Vancouver Coastal Health Foundation, and the Wolridge Foundation.

Dr. Taboulsee reports receiving grant funding from Bayer, Biogen, the Canadian Institute for Health Research, the Lotte and John Hecht Foundation, Roche, and the Vancouver Hospital Foundation; serving on the data safety monitoring board for Merck Serono and the clinical trial steering committee for Roche; and receiving honoraria or travel grants from Biogen, Chugai Pharmaceuticals, Merck/EMD Serono, Roche, and Teva Canada Innovation.

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